A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis.

Zhao T, Wang D, Cheranov SY, Karpurapu M, Chava KR, Kundumani-Sridharan V, Johnson DA, Penn JS, Rao GN
J Lipid Res. 2009 50 (3): 521-33

PMID: 18849464 · PMCID: PMC2638108 · DOI:10.1194/jlr.M800388-JLR200

To investigate the mechanisms underlying 15(S)-HETE-induced angiogenesis, we have studied the role of the small GTPase, Rac1. We find that 15(S)-HETE activated Rac1 in human retinal microvascular endothelial cells (HRMVEC) in a time-dependent manner. Blockade of Rac1 by adenovirus-mediated expression of its dominant negative mutant suppressed HRMVEC migration as well as tube formation and Matrigel plug angiogenesis. 15(S)-HETE stimulated Src in HRMVEC in a time-dependent manner and blockade of its activation inhibited 15(S)-HETE-induced Rac1 stimulation in HRMVEC and the migration and tube formation of these cells as well as Matrigel plug angiogenesis. 15(S)-HETE stimulated JNK1 in Src-Rac1-dependent manner in HRMVEC and adenovirus-mediated expression of its dominant negative mutant suppressed the migration and tube formation of these cells and Matrigel plug angiogenesis. 15(S)-HETE activated ATF-2 in HRMVEC in Src-Rac1-JNK1-dependent manner and interference with its activation via adenovirus-mediated expression of its dominant negative mutant abrogated migration and tube formation of HRMVEC and Matrigel plug angiogenesis. In addition, 15(S)-HETE-induced MEK1 stimulation was found to be dependent on Src-Rac1 activation. Blockade of MEK1 activation inhibited 15(S)-HETE-induced JNK1 activity and ATF-2 phosphorylation. Together, these findings show that 15(S)-HETE activates ATF-2 via the Src-Rac1-MEK1-JNK1 signaling axis in HRMVEC leading to their angiogenic differentiation.

MeSH Terms (18)

Activating Transcription Factor 2 Cell Differentiation Cells, Cultured Collagen Drug Combinations Endothelial Cells Humans Hydroxyeicosatetraenoic Acids Laminin Mitogen-Activated Protein Kinase 8 Models, Biological Neovascularization, Pathologic Proteoglycans rac1 GTP-Binding Protein Retinal Neovascularization Retinal Vessels Signal Transduction src-Family Kinases

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